Abstract
Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2733-27339 |
| Number of pages | 24607 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 15 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
IQGAP1 scaffold-MAP kinase interactions enhance multiple myeloma clonogenic growth and self-renewal. / Gocke, Christian; McMillan, Ross; Wang, Qiuju; Begum, Asma; Penchev, Vesselin R.; Ali, Syed Abbas; Borrello, Ivan M; Huff, Carol Ann; Matsui, William.
In: Molecular Cancer Therapeutics, Vol. 15, No. 11, 01.11.2016, p. 2733-27339.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IQGAP1 scaffold-MAP kinase interactions enhance multiple myeloma clonogenic growth and self-renewal
AU - Gocke, Christian
AU - McMillan, Ross
AU - Wang, Qiuju
AU - Begum, Asma
AU - Penchev, Vesselin R.
AU - Ali, Syed Abbas
AU - Borrello, Ivan M
AU - Huff, Carol Ann
AU - Matsui, William
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.
AB - Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Selfrenewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif-containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.
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UR - http://www.scopus.com/inward/citedby.url?scp=84995421887&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0323
DO - 10.1158/1535-7163.MCT-16-0323
M3 - Article
C2 - 27573425
AN - SCOPUS:84995421887
VL - 15
SP - 2733
EP - 27339
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 11
ER -